Activated pyruvate

The 2,2-bis(tnfluoromethyl)-4-methyl-2f/-5-oxazolone, readily available from 2,2-bis(trifluoromethyl)-l,3-oxazolidin-5-one, is a synthetic equivalent of activated pyruvate [90] (equation 16). 

Acetyl-CoA is a potent allosteric effector of glycolysis and gluconeogenesis. It allosterically inhibits pyruvate kinase (as noted in Chapter 19) and activates pyruvate carboxylase. Because it also allosterically inhibits pyruvate dehydrogenase (the enzymatic link between glycolysis and the TCA cycle), the cellular fate of pyruvate is strongly dependent on acetyl-CoA levels. A rise in... 

Between meals when fatty acids are oxidized in the liver for energy, accumulating acetyl CoA activates pyruvate carboxylase and gluconeogenesis and inhibits PDH, thus preventing conversion of lactate and alanine to acetyl CoA. 

The FADHj and NADH are oxidized in the electron transport chain, providing ATP. In musde and adipose tissue, the acetyl CoA enters the citric acid cyde. In liver, the ATP may be used for gluconeogenesis, and the acetyl CoA (which cannot be converted to glucose) stimulates gluco-neogenesis by activating pyruvate carboxylase. 

Answer B. Acetyl CoA activates pyruvate carboxylase and gluconeogenesis during fasting. 

High acetyl CoA levels from 3-oxidation of fatty acids in liver cells inhibit the pyruvate dehydrogenase complex and activate pyruvate carboxylase, which increases oxaloacetate synthesis. 

Note that the C02 added to pyruvate in the pyruvate carboxylase step is the same molecule that is lost in the PEP carboxykinase reaction (Fig. 14-17). This carboxylation-decarboxylation sequence represents a way of activating pyruvate, in that the decarboxylation of oxaloacetate facilitates PEP formation. In Chapter 21 we shall see how a similar carboxylation-decarboxylation sequence is used to activate acetyl-CoA for fatty acid biosynthesis (see Fig. 21-1). 

Feed-forward regulation In liver, pyruvate kinase is activated by fructose 1,6-bisphosphate, the product of the phosphofructo-kinase reaction. This feed-forward (instead of the more usual feedback) regulation has the effect of linking the two kinase activities increased phosphofructokinase activity results in elevated levels of fructose 1,6-bisphosphate, which activates pyruvate kinase. 

During a fast, the liver is flooded with fatty acids mobilized from adipose tissue. The resulting elevated hepatic acetyl CoA produced primarily by fatty acid degradation inhibits pyruvate dehydrogenase (see p. 108), and activates pyruvate carboxylase (see p. 117). The oxaloacetate thus produced is used by the liver for gluconeogenesis rather than for the TCA cycle. Therefore, acetyl Co A is channeled into ketone body synthesis. 

The cycle oxidizes acetyl-CoA, and to perform this task, it must convert acetyl-CoA to citrate. For this to be achieved, oxaloacetate must be available. If the removal of intermediates results in a decrease in the amount of oxaloacetate for this purpose, acetyl-CoA cannot be removed and will accumulate. This will inhibit the pyruvate dehydrogenase complex and activate pyruvate carboxylase, leading to the conversion of pyruvate to oxaloacetate. This product is now available to condense with the acetyl-CoA to produce citrate, which will restore the status quo. Reactions like that of pyruvate carboxylase that provide molecules for the replacement of intermediates of the citric acid cycle are known as anaplerotic reactions (Greek, meaning to fill up ana = up + plerotikos from pleroun = to make full ). 

Regulation of Pyruvate Dehydrogenase Activity Pyruvate dehydrogenase is the key enzyme that commits pyruvate (and hence the products of carbohydrate metabolism) to complete oxidation (via the tricarboxyUc acid cycle) or lipogenesis. It is subject to regulation by both product inhibition and a phosphorylation/dephosphorylation mechanism. Acetyl CoA and NADH are both inhibitors, competing with coenzyme A and NAD+. 

In addition to its cofactor role, thiamin diphosphate, together with calcium or other divalent cations, activates pyruvate dehydrogenase by binding to a regulatory site and reducing the for pyruvate (Czerniecki and Czygier, 2001). 

A third fate of pyruvate is its carboxylation to oxaloacetate inside mitochondria, the first step in gluconeogenesis. This reaction and the subsequent conversion of oxaloacetate into phosphoenolpyruvate bypass an irreversible step of glycolysis and hence enable glucose to be synthesized from pyruvate. The carboxylation of pyruvate is also important for replenishing intermediates of the citric acid cycle. Acetyl CoA activates pyruvate carboxylase, enhancing the synthesis of oxaloacetate, when the citric acid cycle is slowed by a paucity of this intermediate. 

In positive feedforward, earlier reactants in a metabolic sequence feed-forward positively on later steps. If A is accumulating, it makes sense to speed up downstream reactions to use it up, e.g., ft-uctose-l,6-bisphosphate activates pyruvate kinase in glycolysis. A combination of feedback and feedforward is used to regulate enzyme activity (Fig. 6.10). 

Insulin stimulates phosphatases that dephosphoiylate and activate pyruvate kinase. 

Some other recent contributions to the carbohydrate metabolism in fish may also be mentioned the description of the occurrence in fish muscle of the K-activated pyruvic phosphopherase already described in mammalian muscle (Boyer, 1953), the observation of the glycolytic activity of the swim bladder gland (Strittmatter, Ball, and Cooper, 1952), the study of the respiration and glycolysis of the retinal tissues of fishes (De Vincentiis, 1952). 

Fully activated pyruvate carboxylase depends upon the presence of... 

Sprince, Josephs and Wilpizeski measured the effects of y-hydroxybutyric acid and several related compounds by noting loss of righting reflex after intraperitoneal injection in rats. y-Butyrolactone was active more quickly and for a longer time than equivalent amounts of the acid. 1, 4-Butanediol was comparable in activity to the acid, but 1, 3-butanediol was much less active. Pyruvate prevented or reversed the ERR effect of the acid, the lactone and the 1, 4-diol. 

Sodium dichloroacetate (DCA) is a small molecule that has multiple effects on intermediary metabolism. Of primary interest in the current example is the ability of DCA to activate pyruvate dehydrogenase, the rate-limiting enzyme for the conversion of pyruvate to acetyl CoA. The pyruvate concentration is, in turn, replenished by oxidation of lactate, thereby replenishing concentrations of the latter. Such a reduction may decrease the morbidity in head trauma, where local (CSF) elevated lactate is thought to be neurotoxic. 

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